Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluoromethylene) cytidine, a novel inhibitor of ribonucleoside diphosphate reductase, on human colon carcinoma xenografts in nude mice

• Published in: Cancer research (Chicago, Ill.) Ill.), 1997-09, Vol.57 (18), p.4023-4028
• Main Authors: SUN, L.-Q, LI, Y.-X, GUILLOU, L, MIRIMANOFF, R.-O, COUCKE, P. A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Carcinoma - drug therapy; Carcinoma - pathology; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Humans; Injections, Intraperitoneal; Injections, Intravenous; Leukocyte Count; Liver Neoplasms - secondary; Medical sciences; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Pharmacology. Drug treatments; Radiation-Sensitizing Agents - pharmacology; Ribonucleotide Reductases - antagonists & inhibitors; Survival Analysis; Transplantation, Heterologous
• ISSN: 0008-5472; 1538-7445

Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. xenografts and liver metastases of a human colon carcinoma. FMdC given once daily or twice weekly has a dose-dependent antitumor effect. The maximum tolerated dose in the mice was reached with 10 mg/kg applied daily over 12 days. Twice weekly administration of FMdC reduced its toxicity but lowered the antitumor effect. Treatment of preestablished liver micrometastases obtained via intrasplenic injection of tumor cells, with 5 or 10 mg/kg FMdC, significantly prolonged the survival of the mice as compared to controls (P < 0.025 and P < 0.001, respectively). Ten mg/kg resulted in longer survival than 5 mg/kg FMdC (P < 0.05). Radiotherapy alone of s.c. xenografts (10 fractions over 12 days) yielded the radiation dose required to produce local tumor control in 50% of the treated mice (TCD50) of 43.0 Gy. When combined with FMdC, TCD50 was reduced to 22.5 and 19.0 Gy at doses of 5 and 10 mg/kg given i.p. 1 h before each irradiation, respectively. The corresponding enhancement ratios were 1.91 and 2.43, respectively. FMdC produced moderate and reversible myelosuppression. When 5 mg/kg FMdC was combined with irradiation, there was no increased skin or hematological toxicity as compared to radiotherapy or FMdC alone. At the 10 mg/kg level, however, lower leukocyte counts were observed. These results show that FMdC appears to be a potent anticancer drug and radiosensitizer.